1. Field of the Invention
This invention relates to the production of a biologic composition that reduces blood pressure, and to the use of such compositions in lowering elevated arterial pressure in subjects.
2. Description of the Background Art
An elevated arterial pressure (i.e., hypertension, high blood pressure) is probably the most important public health problem in developed countries--being common, asymptomatic, readily detectable, and often leading to lethal complications if left untreated. Williams, G. H., et al.. In: Harrison's Principles of Internal Medicine, 10th ed., Petersdorf, R. G., et al.. eds., McGraw-Hill, New York, 1983, chapter 247.
Hypertensive patients are classified into two broad categories. A relatively small proportion of patients develop hypertension as a manifestation of an identifiable and specifically treatable underlying cause, such as pheochromocytoma, renal arterial stenosis, or endocrine disease. Such patients are denominated as exhibiting secondary hypertension.
From 80-95% of patients with sustained elevated arterial pressure have no discernible underlying causative factor. These patients are said to have essential or primary or idiopathic hypertension.
The etiology of essential hypertension is almost certainly multifactorial. Such factors include the sympathetic and parasympathetic nervous systems, baroreceptor function, and the reninangiotensin-aldosterone and the atrial natriuretic factor systems that control renal sodium and water flux. In addition, genetic and cardiovascular risk factors such as obesity, hypercholesterolemia, diabetes, salt intake, occupation, and cigarette smoking have long been assumed to be important in the genesis of essential hypertension.
Whatever the etiology of the disease, patients with untreated hypertension die prematurely, most commonly due to heart disease, but with strokes and renal failure often frequently occurring. As a result of clinical trials, there is firm evidence that reducing diastolic blood pressure that is above 90 mm Hg in middle-aged patients is associated with a decrease in cardiovascular morbidity and mortality. Blaschke, T. F., et al.. In: Goodman and Gilman's The Pharmacological Basis of Therapeutics, Gilman, A. G., et al.. eds., McMillan, New York, 1980, chapter 32.
Current treatments of hypertension consist of general measures and specific measures. General measures include dietary control and elimination of cardiovascular risk factors such as overweight, cigarette smoking, high salt intake, stress, etc.
Specific measures for treating hypertension consist of therapy with antihypertensive drugs. Many clinical studies have demonstrated that in almost all cases of hypertensive cardiovascular disease, the blood pressure can be successfully controlled by skillful use of the drugs currently available. However, it has also been estimated that only a small percentage of all hypertensive patients under treatment are even close to optimal control. Thus, effective use of antihypertensive drugs is not "routine," and therapy must be tailored to the individual patient and be adjusted as necessary to maintain an optimal balance between the therapeutic effects and the well-known adverse side effects associated with currently-employed antihypertensive drugs. Blaschke et al.. supra at 809.
There are four classes of hypertensive drugs currently being used, each directed to a different mechanism of disease. These classes include: diuretics, anti-adrenergic agents, vasodilators, and angiotensin blockers. Each is therapeutically effective in appropriate patients, but each may produce severe adverse side effects; all are expensive.
The popular thiazine diuretics are quickly effective, but may produce undesirable side effects such as hypokalemia, hypouricemia, and carbohydrate intolerance. Anti-adrenergic drugs (i.e., "beta blockers") are effective in certain types of hypertension, i.e., when there is increased cardiac sympathetic nerve activity, but such drugs may precipitate congestive heart failure and asthma, and must be used with caution in diabetics; other side effects include dizziness, depression, nausea, vomiting, diarrhea, and constipation. Vasodilators, which act primarily on arterial resistance rather than on venous capacitance, are effective against hypertension, but the effects of such agents are unfortunately negated by reflex increases in sympathetic discharges that raise heart rate and cardiac output. Thus, vasodilators are contraindicated in severe coronary artery disease, and are also known to produce undesirable side effects such as headache, tachycardia, angina pectoris, anoxia, nausea, vomiting, diarrhea, and a lupus-like syndrome. Angiotensin blockers are promising, but frequent side effects include leukopenia, pancytopenia, proteinuria, nephrotic syndrome, rash, fever, and loss of taste. Williams et al.. supra at 1485.
In all but the mildly hypertensive patient who responds favorably to a diuretic or to a beta blocker, combinations of drugs are used. A successful combination is one whose components give additive or synergistic therapeutic effects, while causing minimal toxicity. Ideally, therapy should lower blood pressure effectively without producing side effects that become so unacceptable to the patient that compliance to the regimen is threatened or that compromise of the vital functions of the brain, heart, or kidneys.
A very difficult and important problem in the drug therapy of hypertension is to determine what constitutes "acceptable" side effects. All the effective antihypertensive drugs can produce quite significant adverse effects, to the extent where, in clinical trials, patients reported feeling better with the placebo than with the antihypertensive drug. Blaschke et al.. supra at 809.
In view of these shortcomings, the limitations to the antihypertensive drug therapy known to the prior art are readily apparent. It would be highly desirable, therefore, to have an antihypertensive agent that is inexpensive, readily available, derived from a natural source, easily administered, highly effective against hypertension, and devoid of undesirable side effects. The hyperimmune bovid milk of the present invention is such an antihypertensive agent.
It has been known in the prior art to produce milk having a variety of therapeutic effects. Beck, for example, has disclosed a milk containing antibody to Staphylococcus mutans that has dental caries-inhibiting effects (Beck, U.S. Pat. No. 4,324,784; British Patent 1,505,513). The milk is obtained by hyperimmunization of a cow with Streptococcus mutans antigen and collecting the therapeutic milk therefrom. Beck has also described a milk having anti-arthritic properties (copending U.S. application Ser. No. 875,140, filed Feb. 6, 1978), and has patented a method of treating inflammation using milk from hyperimmunized cows (Beck, U.S. Pat. No. 4,284,623). Stolle has disclosed a method of using milk from a hyperimmunized cow to treat diseases of the vascular and pulmonary systems (Stolle et al.. U.S. Pat. No. 4,636,384). Heinbach, U.S. Pat. No. 3,128,230, has disclosed milk containing alpha, beta and gamma globulins against anti-9-enic haptens. Singh (U.S. Pat. No. 3,911,108), Peterson (U.S. Pat. No. 3,376,198 and Canadian Patent 587,849), Holm (U.S. Application (published) Ser. No. 628,987), Tannah et al. (British Patent 1,211,876), and Biokema S. A. (British Patent 1,442,283) have also described antibody-containing milks. Steffkoff et al., Minerva Medica Italy) 56:4163-4 (1965) have described the treatment of hypertensive diseases with sour milk.
It is well known to those skilled in the art of immunology that serum globulin fractions consisting of various antibody types such as IgA, IgG, and IgM can be used to counter the corresponding antigens, thereby neutralizing the effects of the antigens. There is an almost infinite number of harmful antigens to which animals can be exposed, including carcinogenic, bacterial, viral, and regulatory factors of plant and animal origin, as well as toxins and poisons.
Normally, upon exposure to a foreign antigen, e.g., a bacterium, the immune system of the host will produce antibodies that will neutralize the effects of the antigen. Exposure to such foreign antigens can occur either naturally, or deliberately by administration of the antigen in vaccine form. The latter is generally referred to as active immunization of the host species exposed to the antigen. The antibodies produced in response to such vaccination are homologous to said given species of animal, and are epitopic to the antigen.
In copending related patent applications, U.S. application Ser. No. 546,162, filed Oct. 27, 1983, and U.S. application Ser. No. 001,848, filed Jan. 9, 1987, there was disclosed a method of lowering blood lipid levels and treating lipid-associated vascular disorders, as well as treating macrophage-related pulmonary disorders, comprising feeding test animals and humans antibody-containing milk derived from cows maintained in a hyperimmune state by injections of polyvalent antigens derived from mixtures of killed bacteria. In another copending application (U.S. application Ser. No. No. 069,139, filed Jul. 2, 1987), there was disclosed use of antibody-containing milk derived from hyperimmunized cows for the treatment of gastrointestinal disorders. The present invention is a further development over the inventions disclosed and claimed in the aforementioned applications, the entire disclosures of which are herein incorporated by reference.
All of these references, however, relate only to the isolation from hyperimmunized animals of immunoglobulins raised against various antigens and to the subsequent use of said antigens for either diagnostic procedures, homologous or heterologous passive immunization, or active immunization. No suggestion or speculation is made in any of these references that milk derived from hyperimmunized bovids is useful in lowering arterial blood pressure.